O-Desmethylvenlafaxine is predominantly active metabolite of venlafaxine and has been shown to inhibit norepinephrine and serotonin uptake. O-Desmethylvenlafaxine succinate marketed in US as PRISTIQ™ and chemically known as 1[2-(dimethylamino)-1-(4-phenol)ethyl]cyclohexanol has the following structure.

U.S. Pat. No. 4,535,186 filed on Oct. 26, 1983 and granted on Aug. 13, 1985 and assigned to American Home Products corporation claims O-desmethylvenlafaxine as a product and discloses a method of preparation of the same. O-desmethylvenlafaxine is prepared by reacting p-methoxyphenyl acetonitrile with cyclohexanone in the presence of n-butyl lithium at −50° C. in tetrahydrofuran followed by workup to give 1-[cyano(p-methoxyphenyl)methyl]-cyclohexanol. Subsequently, it is subjected to reduction reaction in presence of Rhodium under hydrogen pressure to give 1-[2-amino-1-(p-methoxyphenyl)ethyl]cyclohexanol, followed by alkylation reaction in presence of formaldehyde and formic acid to give venlafaxine and further subjected to O-demethylation to give the O-desmethylvenlafaxine.
According to the prior art processes, p-methoxyphenyl acetonitrile is reacted with cyclohexanone in presence of strong base such as butyl lithium at −80° C. to −50° C. to give 1-[cyano(p-methoxyphenyl)methyl]cyclohexanol. The handling of n-butyl lithium during large scale production at plant level is difficult and poses a fire hazard. Further this reaction is carried out at lower temperature around −80° to −50° C. and the use of strong base such as n-butyl lithium during the condensation reaction results in formation of more impurities. The crude mass so obtained requires repeated crystallization steps to get the desired quality of the product.
WO 2007/094008 application discloses a process for the preparation of O-desmethylvenlafaxine, wherein p-methoxyphenyl acetonitrile is reacted with cyclohexanone in presence of sodium hydroxide and phase transfer catalyst selected from polyethyleneglycol-400 or ALIQUATE 336™ (N-methyl-N,N-dioctyloctan-1-ammonium chloride) to give 1-cyano[(4-methoxyphenyl)methyl] cyclohexanol, which is further subjected to reduction reaction in the presence of reducing agent such as borane-dimethylsulphide complex, aluminum chloride-sodium borohydride to give 1-[2-amino-1-(4methoxyphenyl)ethyl]cyclohexanol. Subsequently, 1-[2-amino-1-(4-methoxyphenyl)ethyl]cyclohexanol is subjected to reductive aviation reaction in presence of formic acid and formaldehyde to give venlafaxine.
Existing processes for the preparation of O-Desmethylvenlafaxine involve use of hazardous chemicals and produces impure O-desmethylvenlafaxine with less yield thereby requiring multiple purification steps that add up to the cost of the final product.
Therefore, there exists a need to develop an alternate and improved process for the preparation of O-desmethylvenlafaxine with improved yield. Further the process involves use of non hazardous chemicals and is simple, convenient and cost-effective for large scale production.